The Medical Breast Cancer Section now has two clinical trials exploring the use of gene transfer into human hematopoietic stern cells following treatment of breast cancer patients with high dose ICE chemotherapy and stem cell transfer. In collaboration with Dr. Cindy Dunbar five breast cancer patients that have been treated with high dose ICE chemotherapy and autologous stem cells that have been transduced ex vivo with the neomycin resistance (NeoR) gene. This study has demonstrated that human CD34+ cells can be transduced in vitro with a retroviral vector expressing the NeoR gene and that NeoR-marked cells can be detected in patients peripheral blood and bone marrow for over a year following reconstitution in all hematopoietic cell lineages. We are currently examining different transduction conditions in an attempt to increase the efficiency of hematopoietic stem cell gene transfer ex vivo. We have also begun a gene therapy protocol in for breast cancer patients undergoing ICE chemotherapy and stem cell transfer in which CD34+ selected cells are transduced with a retroviral vector expressing the multidrug resistance gene mdr- l. The ability of the mdr-1 transduced stem cells to "resist" chemotherapy induced myelotoxicity following hematopoietic reconstitution will be examined. We completed a Phase I study of taxol and high dose cyclophosphamide with G-CSF in metastatic breast cancer and found it to be an active regimen in previously treated patients. We completed a clinical trial of GM-CSF vs PIXY following FLAC chemotherapy for patients with breast cancer and failed to show any benefit from the PIXY fusion cytokine. We also completed a Phase I study of taxol plus R-verapmil in order to study the effects of this drug resistance modulator in breast cancer. We have initiated a Phase I study of 14 d infusional taxol and pilot study of high-dose, short course therapy with cytoxan and adriamycin and infusional taxol was started in stage II, III breast cancer patients. We have also begun new clinical trials in chemoprevention of breast cancer in high risk patients including patients that carry BRCA1 mutations involves treatment. Patients are treated with tamoxifen and fenretinide and laboratory studies on patient biopsies in order to define intermediate surrogate biomarkers of malignant progression and to study phenotypic and genotypic alterations occurring in mammary epithelial cell lines obtained from high risk patients.